Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial.
Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial.
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DOI：
10.1016/s1470-2045(17)30909-9
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发表时间：
2018-01
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影响因子：
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通讯作者：
Byrd JC
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作者：
Jones JA;Mato AR;Wierda WG;Davids MS;Choi M;Cheson BD;Furman RR;Lamanna N;Barr PM;Zhou L;Chyla B;Salem AH;Verdugo M;Humerickhouse RA;Potluri J;Coutre S;Woyach J;Byrd JC
使用依鲁替尼靶向布鲁顿酪氨酸激酶 (BTK) 的疗法已经改变了慢性淋巴细胞白血病 (CLL) 的治疗方法。依鲁替尼治疗后难治或复发的患者预后不佳。 Venetoclax 是一种选择性、口服生物可利用的 BCL-2 抑制剂，对经过大量治疗的复发/难治性 CLL 患者具有活性。这项二期、多中心、开放标签研究旨在评估 Venetoclax 对于伊布替尼治疗期间或之后复发的难治性 CLL 患者的疗效和安全性。年龄至少 18 岁的患者，如果需要根据 2008 年慢性淋巴细胞白血病国际研讨会 (iwCLL) 的标准进行治疗，东部肿瘤合作组表现评分≤2，骨髓功能充足（无论生长因子支持如何，中性粒细胞绝对计数≥1,000/μL，血小板计数≥30,000/mm3，血红蛋白≥8，则有资格参加研究g/dL)，肌酐清除率≥50 mL/min。在研究开始时，所有患者都通过正电子发射断层扫描筛查了里氏转化，如果活检证实了里氏转化，则被排除在外。患者接受 Venetoclax 治疗，起始剂量为每日 20 毫克，并在五周内逐步增加剂量至每日 400 毫克的目标剂量。对于疾病快速进展的患者，采用加速给药方案。治疗持续直至疾病进展或因其他原因停止。该研究的主要目的是评估维奈托克单一疗法的有效性和安全性。疗效通过总体缓解率来衡量，总体缓解率定义为根据研究者根据 iwCLL 标准进行的评估获得总体缓解的患者比例。通过不良事件监测和实验室评估来评估安全性。这项研究正在进行中，根据监管机构的要求收集了截至 2017 年 6 月 30 日的中期分析数据，其中包括所有接受至少一剂维奈托克的患者。该试验在 ClinicalTrials.gov 上注册，注册号为 NCT02141282。 2014 年 9 月至 2016 年 11 月期间，从美国 15 个地点招募了患者。该研究纳入了 91 名既往接受过依鲁替尼治疗的患者，其中 43 名属于主队列，48 名属于扩展队列。在分析时，所有 91 名患者的中位研究时间（即随访）为 14 个月（范围：0·1–31；IQR：8–18），主要队列中的 43 名患者为 19 个月（范围：0·1–26；IQR：9–27），扩展中的 48 名患者为 12 个月（范围：0·1–18；IQR：8–15）。队列。 91 名患者中有 59 名 (65%) 获得客观缓解（95% CI：53%、74%。主要队列：43 名患者中的 30 名 [70%]，95% CI：54%；83%；扩展队列：48 名患者中的 29 名 [60%]，95% CI：43%、72%）。 91 名患者中有 8 名（9%）获得完全缓解。常见的3级或4级不良事件（发生在2名以上患者中）包括中性粒细胞减少症（91名患者中的46名[51%]）、血小板减少症（91名患者中的26名[29%]）、贫血（91名患者中的26名[29%]）、白细胞计数减少（91名患者中的17名[19%]）、淋巴细胞计数减少（91名患者中的17名[19%]） [91 名患者中的 15%]）、发热性中性粒细胞减少症（91 名患者中的 12 名 [13%]）、低磷酸血症（91 名患者中的 12 名 [13%]）、腹泻（91 名患者中的 6 名 [7%]）、疲劳（91 名患者中的 6 名 [7%]）、肺炎（91 名患者中的 6 名 [7%]）、低钠血症（91 名患者中的 6 名 [7%]） 91 名患者）、高血压（91 名患者中 6 名 [7%]）、高血糖（91 名患者中 5 名 [5%]）、低钾血症（91 名患者中 5 名 [5%]）、腹痛（91 名患者中 4 名 [4%]）、淋巴细胞计数增加（91 名患者中 4 名 [4%]）、缺氧（91 名患者中 4 名 [4%]）、蜂窝组织炎（91 名患者中的 3 名 [3%]）、跌倒（91 名患者中的 3 名 [3%]）、丙氨酸转氨酶升高（91 名患者中的 3 名 [3%]）、低钙血症（91 名患者中的 3 名 [3%]）、自身免疫性溶血性贫血（91 名患者中的 2 名 [2%]）、白内障（91 名患者中的 2 名 [2%]）、肺部感染（91 名患者中 2 名 [2%]）、尿路感染（91 名患者中 2 名 [2%]）、天冬氨酸转氨酶升高（91 名患者中 2 名 [2%]）、脱水（91 名患者中 2 名 [2%]）、高钙血症（91 名患者中 2 名 [2%]）、低蛋白血症（91 名患者中 2 名 [2%]）、晕厥（91 名患者中 2 名 [2%]） 91 名患者中 2 名 [2%]），以及呼吸困难（91 名患者中 2 名 [2%]）。 91 名患者中有 17 名（19%）死亡，其中 7 名因疾病进展而死亡；最后一剂 Venetoclax 后 30 天内发生 7 例死亡，原因包括疾病进展、棒状杆菌脓毒症、多器官衰竭、感染性休克、后续治疗中可能出现的细胞因子释放综合征、机械性窒息，且死亡原因不明。这些死亡均未归因于维奈托克治疗。维奈托克对于在先前使用依鲁替尼治疗期间或之后疾病进展的 CLL 患者表现出持久的临床活性和良好的耐受性。
Therapy targeting Bruton’s tyrosine kinase (BTK) with ibrutinib has transformed treatment for chronic lymphocytic leukaemia (CLL). Patients who are refractory or relapse after ibrutinib experience poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 that has activity in heavily-pretreated patients with relapsed/refractory CLL. This phase two, multicentre, open-label study was conducted to evaluate the efficacy and safety of venetoclax for patients with CLL refractory to or who relapsed during or after ibrutinib. Patients at least 18 years of age were eligible for study enrollment if they required therapy according to criteria from the 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL), had an Eastern Cooperative Oncology Group performance score of ≤2, adequate bone marrow function (absolute neutrophil count ≥1,000/μL irrespective of growth factor support, platelet count ≥30,000/mm3, hemoglobin ≥8 g/dL), and creatinine clearance ≥50 mL/min. At study entry, all patients were screened for Richter’s transformation by positron emission tomography and were excluded if Richter’s transformation was confirmed on biopsy. Patients received venetoclax starting at 20mg daily with stepwise dose ramp-up over five weeks to the target 400mg daily dose. For patients with rapidly-progressing disease, an accelerated schedule of administration was utilized. Treatment continued until disease progression or discontinuation due to other reasons. The primary objective of the study was to evaluate the efficacy and safety of venetoclax monotherapy. Efficacy was measured by overall response rate, defined as the proportion of patients with an overall response based on the investigator’s assessment per iwCLL criteria. Safety was evaluated via adverse event monitoring and laboratory assessments. This study is ongoing and data for this interim analysis per regulatory agency request were collected as of June 30, 2017 and included all patients who received at least one dose of venetoclax. This trial was registered at ClinicalTrials.gov, number NCT02141282. Patients were recruited from 15 sites across the United States between September 2014 and November 2016. The study enrolled 91 patients who previously received ibrutinib, 43 in the main cohort and 48 in the expansion cohort. At the time of analysis, the median time on study (ie, follow up) was 14 months (range: 0·1–31; IQR: 8–18) for all 91 patients, 19 months (range: 0·1–26; IQR: 9–27) for 43 patients in the main cohort, and 12 months (0·1–18; IQR: 8–15) for 48 patients in the expansion cohort. An objective response was achieved in 59 (65%) of 91 patients (95% CI: 53%, 74%. Main cohort: 30 [70%] of43, 95% CI: 54%; 83%; expansion cohort: 29 [60%] of 48, 95% CI: 43%, 72%). Eight (9%) of 91 patients achieved complete remission. Common grade 3 or 4 adverse events of (occurring in more than 2 patients) included neutropenia (in 46 [51%] of 91 patients), thrombocytopenia (in 26 [29%] of 91 patients), anaemia (in 26 [29%] of 91 patients), decreased white blood cell count (in 17 [19%] of 91 patients), decreased lymphocyte count (in 14 [15%] of 91 patients), febrile neutropenia (12 [13%] of 91 patients), hypophosphataemia (in 12 [13%] of 91 patients), diarrhoea (in 6 [7%] of 91 patients), fatigue (in 6 [7%] of 91 patients), pneumonia (in 6 [7%] of 91 patients), hyponatraemia (in 6 [7%] of 91 patients), hypertension (in 6 [7%] of 91 patients), hyperglycaemia (in 5 [5%] of 91 patients), hypokalaemia (in 5 [5%] of 91 patients), abdominal pain (in 4 [4%] of 91 patients), increased lymphocyte count (in 4 [4%] of 91 patients), hypoxia (in 4 [4%] of 91 patients), cellulitis (in 3 [3%] of 91 patients), fall (in 3 [3%] of 91 patients), increased alanine aminotransferase (in 3 [3%] of 91 patients), hypocalcaemia (in 3 [3%] of 91 patients), autoimmune haemolytic anaemia (in 2 [2%] of 91 patients), cataract (in 2 [2%] of 91 patients), lung infection (in 2 [2%] of 91 patients), urinary tract infection (in 2 [2%] of 91 patients), increased aspartate aminotransferase (in 2 [2%] of 91 patients), dehydration (in 2 [2%] of 91 patients), hypercalcaemia (in 2 [2%] of 91 patients), hypoalbuminaemia (in 2 [2%] of 91 patients), syncope (in 2 [2%] of 91 patients), and dyspnoea (in 2 [2%] of 91 patients). Seventeen (19%) of 91 patients died, with 7 due to disease progression; seven deaths occurred within 30 days after the last dose of venetoclax due to disease progression, Corynebacterium sepsis, multi-organ failure, septic shock, possible cytokine release syndrome on subsequent therapy, mechanical asphyxia, and one cause of death was unknown. None of these deaths were attributed to treatment with venetoclax.. Venetoclax showed durable clinical activity and favourable tolerability in patients with CLL whose disease progressed during or after prior treatment with ibrutinib.